Research Roundup: November 2, 2018

Melanoma immunotherapy from two cells' points of view, drugging undruggable cancer targets, listening to gut cells talk to each other, and more.

Erik Jacobs
Credit: Erik Jacobs

Welcome to the November 2, 2018 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Eavesdropping on gut gossip

The gut's intestinal stem cells (ISCs) "talk" to other cell types to help maintain a robust and healthy cellular community. In this week's Cell, Moshe Biton, Adam Haber, Noga Rogel, Klarman Cell Observatory (KCO) director and core institute member Aviv Regev, Infectious Disease and Microbiome Program co-director and core institute member Ramnik Xavier, and colleagues dive into one such conversation, between ISCs and T helper (Th) cells. They found that some ISCs express MCH II (a surface complex that activates Th cells), while Th cells produce cytokines (chemical messages) that influence ISCs’ behavior. The crosstalk may help maintain the right balance of immune activity in the gut, as well as hardy stem cell pool. Read more in a Broad news story.

A workaround for drugging undruggable cancer targets

Thalidomide and related drugs defeat blood cancers like multiple myeloma by causing the cell to destroy two transcription factors that both feature a particular molecular pattern, a C2H2 ZF motif. Transcription factors in general are considered undruggable, but in this week's Science, Quinn Sievers and institute member Benjamin Ebert from the Broad Cancer Program and colleagues show that thalidomide-like drugs could be the backbone for a new class of cancer-fighting compounds, one that conscripts a protein called cereblon into flagging for destruction many more of the estimated 800 transcription factors with the same motif. Learn more in a Broad news story.

Separating correlation from causation

Geneticists use Mendelian randomization (MR) to test whether mutations that have a causal relationship with one heritable trait or disease may also have a similar effect on a second trait. However, MR struggles with instances of pleiotropy, where one gene influences two or more unrelated traits. To address this limitation, Luke O’Connor and associate member Alkes Price in the Program in Medical and Population Genetics introduce a new approach called latent causal variable (LCV) modeling, which examines whether one given trait is causal for a second via an inferred "latent" mutation. In Nature Genetics, they demonstrate LCV's utility by using it to study 52 disease-associated traits.

Melanoma’s molecular connections to immunotherapy

Immunotherapy has led to remarkable outcomes for some cancer patients — but for many more, cancer cells evade the treatment and continue to spread, for reasons that remain unclear. Two companion studies in Cell this week investigated the molecular underpinnings of immunotherapy response. In one, a team led by the KCO's Livnat Jerby-Arnon, Benjamin Izar, and Regev identified a gene expression pattern that human melanoma cells use to resist immunotherapy, and demonstrated a combination therapy approach that could overcome this resistance. In the other, a team led by the Broad Cell Circuits Program's Moshe Sade-Feldman, Keren Yizhak, and co-director and institute member Nir Hacohen, with Cancer Program institute member Gad Getz, identified specific states of cytotoxic CD8 T cells that are associated with treatment response in melanoma patients. Check out more in press releases from Broad and Massachusetts General Hospital.

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